Ischemic heart disease and failure is a leading cause of mortality worldwide, accounting for 6.9 million deaths in the year 2000 (See, e.g., Michaud et al., JAMA 285:535 (2001)). Heart failure can result from any condition that reduces the ability of the heart to pump blood. Most frequently, heart failure is caused by decreased contractility of the myocardium, resulting from reduced coronary blood flow. Many other factors may result in heart failure, including damage to the heart valves, vitamin deficiency, and primary cardiac muscle disease (See, e.g., Guyton, Human Physiology and Mechanisms of Disease, Third Edition, W. B. Saunders Co., Philadelphia, Pa., 205 (1982)). Heart failure is commonly manifested in association with myocardial infarction. (See, e.g., Dunagan and Ridner, Manual of Medical Therapeutics, Twenty-Sixth Edition, Little, Brown & Co., Boston, 106 (1989)).
The precise physiological mechanisms of heart failure are not entirely understood. However, heart failure is generally believed to involve disorders in several cardiac autonomic properties, including sympathetic, parasympathetic, and baroreceptor responses. (See, e.g., K. Kiuchi et al. (1993) J. Clin. Invest. 91:907).
Myocardial ischemia and infarction cause a precipitous decline in contractile function, which can lead to acute congestive heart failure. Despite major advances in early reperfusion and revascularization strategies, heart failure remains a common complication of acute coronary syndromes and a powerful predictor of mortality (See, e.g., Khot et al., JAMA 290:2174 (2003); Steg et al., Circ 109:494 (2004)). Myocardial contractile dysfunction during ischemia is due, in no small part, to the effects of intracellular acidosis on the contractile machinery. Acidosis directly depresses myocardial force production despite unchanged or increased levels of intracellular calcium (See, e.g., Orchard and Kentish Am J Physiol 258:C967 (1990)). One mechanism responsible for this pH-mediated force decrement is a decrease in the calcium responsiveness of the contractile myofilaments (See, e.g., Orchard and Kentish Am J Physiol 258:C967 (1990); Lee and Allen J Clin Invest 88:361 (1991)). Current methods of treating the heart during heart failure do not render cardiac muscle resistant to the detrimental effects of acidosis and fail to re-sensitize the contractile machinery to calcium signaling.
Therefore, what is needed is a treatment for the heart (e.g., contractile myofilaments) that protects and augments the hearts ability to respond to calcium during ischemia-induced pH changes. Furthermore, better models (e.g., animal models) are needed in order to study the heart's response to calcium signalling while under oxygen deprivation conditions.